Transplanted Tissue Engineered Axonal "Living Scaffolds" Preserve Regenerative Capacity for Muscle Re-innervation Following Peripheral Nerve Injury
Zarina S. Ali, MD; Kevin D. Browne, BS; Kritika S. Katiyar, BS; Justin C Burrell, MS; Franco A. Laimo, MD; C. Joseph Maggiore, MD; Foteini Mourkioti, MD; D. Kacy Cullen, PhD
University of Pennsylvania, Philadelphia, PA
Introduction: Peripheral-nerve-injury (PNI) affects individuals across all age groups and socioeconomic backgrounds often following sports-related injuries, vehicle accidents or exposure to combat situations, among other traumatic events. With current strategies for surgical repair of PNI, recovery of motor and sensory function is generally inadequate owing to a lack of treatments aimed at preserving the regenerative environment of distal nerve segments and the re-innervation capacity of target muscle(s). Indeed, peripheral nerve regeneration is a race against time as long distances for axonal re-growth often requires many months, over which time endogenous Schwann cells (SCs) and myofibers gradually lose their capacity to support axonal regeneration and re-innervation. Also, inadequate bridging strategies across segmental nerve defects can result in diminished axonal-regenerative-capacity, limiting functional recovery.
Methods/Materials: Tissue engineered nerve grafts (TENGs) consisting of living neurons with aligned axonal tracts were cultured in custom-built mechanobioreactors at densities of >100,000 axons and lengths of ?5cm through the controlled process of axon “stretch-growth”. TENG axons mimic the developmental action of “pioneer” axons, where targeted axonal outgrowth can be achieved along pre-existing axonal tracts in vivo. Here, allogeneic TENGs were created at lengths ranging from 1-5cm and used to bridge segmental nerve defects in rats or pigs, with terminal time points ranging from 2 weeks to 9 months. Histological outcomes included axon regrowth, SC presence and alignment, and dorsal root ganglia (DRG) and spinal motor neuron (SMN) health. Functional outcomes, such as nerve conduction and muscle action potentials, were assessed at chronic time points.
Results: The effects of TENGs on preserving host SC regenerative capacity, DRG/SMN health, and myofibers mass in rat and pig models of PNI were evaluated. Axons projecting from TENGs grew along host SCs in denervated nerve segments – a mechanism not possible with autograft repairs – that served to maintain pro-regenerative SC alignment over several months. We found acute improvements in SMN health in animals repaired with TENGs or autografts versus those repaired with acellular nerve guidance tubes (NGTs) or NGTs filled with disorganized (non-stretch-grown) neurons. Finally, improvements in target muscle mass and fiber size distributions in animals repaired with TENGs or autografts were seen versus NGTs alone.
Conclusion: TENGs uniquely act as “living scaffolds” to promote a favorable environment for nerve regeneration by maintaining pro-regenerative capacity of SCs, health of SMNs, and muscle fiber mass, collectively raising the ceiling for potential levels of functional recovery beyond that attainable by conventional surgical repair strategies.
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